Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.
Everolimus long-term use in patients with tuberous sclerosis complex: Four-year update of the EXIST-2 study.
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DOI：
10.1371/journal.pone.0180939
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Budde K
中科院分区：
文献类型：
--
作者：
Bissler JJ;Kingswood JC;Radzikowska E;Zonnenberg BA;Belousova E;Frost MD;Sauter M;Brakemeier S;de Vries PJ;Berkowitz N;Voi M;Peyrard S;Budde K
我们研究了依维莫司对肾血管平滑肌脂肪瘤伴结节性硬化症或散发性淋巴管平滑肌瘤病患者的长期疗效。在EXIST-2（NCT 00790400）的双盲核心阶段取得良好结果后，允许患者接受开放标签依维莫司（扩展阶段）。最初随机分配到依维莫司组的患者继续使用相同剂量;那些接受安慰剂的患者交叉使用依维莫司10 mg/天。剂量调整基于耐受性。主要终点是血管平滑肌脂肪瘤缓解率，定义为在没有新的靶血管平滑肌脂肪瘤的情况下，靶肾血管平滑肌脂肪瘤的总体积较基线减少≥50%，肾体积较最低值增加>20%，血管平滑肌脂肪瘤相关出血分级≥2。关键次要终点是安全性。在接受≥1剂依维莫司治疗的112例患者中，58%（95% CI，48.3%-67.3%）达到血管平滑肌脂肪瘤缓解。几乎所有患者（97%）在研究期间的某个时间点均出现肾脏病变体积缩小。依维莫司暴露的中位持续时间为46.9个月。16例（14.3%）患者在研究的某个时间点发生血管平滑肌脂肪瘤进展。未报告血管平滑肌脂肪瘤相关出血或肾切除术。1例接受依维莫司治疗的患者因右侧疼痛恶化接受栓塞治疗。48%的患者室管膜下巨细胞星形细胞瘤病变缓解，68%的患者皮肤病变缓解。疑似与治疗相关的最常见不良事件为口腔炎（42%）、高胆固醇血症（30.4%）、痤疮（25.9%）、口疮性口腔炎和鼻咽炎（各21.4%）。10例（8.9%）患者因不良事件退出研究。肾功能保持稳定，紧急不良事件的频率通常随时间推移而降低。依维莫司治疗在大约4年内保持安全有效。总体风险/获益评估支持使用依维莫司作为结节性硬化症或散发性淋巴管平滑肌瘤病相关的血管平滑肌脂肪瘤的可行治疗选择。ClinicalTrials.gov NCT00790400
We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Following favorable results from the double-blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety. Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time. Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. ClinicalTrials.gov NCT00790400
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影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
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Franz, David Neal
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Takeda, K
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Bissler, John J.;Kingswood, J. Christopher;Budde, Klemens
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Budde, Klemens